PROJECT SUMMARY/ABSTRACT The goal of this career development award is to interrogate the relationship between prenatal stress, placental microbes, intrauterine inflammation and growth factors, and investigate their influence on the development of aberrant behavior in exposed offspring. The proposal is designed to facilitate the career development and transition to independence of Tamar L. Gur, M.D., Ph.D., a board certified, practicing psychiatrist, specializing in the treatment of perinatal depression and anxiety. At the conclusion of the award, Dr. Gur will be an independent investigator, leading a transdisciplinary research laboratory that will make substantial contributions to the understanding of the influence of prenatal stress on psychiatric disorders in offspring, by probing the interplay between stress, microbes, inflammation and growth factors in the intrauterine environment, using innovative methods. Dr. Gur will gain this expertise through the combined guidance of her primary mentor, Dr. Michael Bailey, PhD, a leader in stress and the microbiome, and co-mentor, Dr. Irina Buhimschi, MD, an expert in the molecular mechanisms underlying pathophysiology in pregnancy, and mouse models of pregnancy. Prenatal stress is a known contributor to the emergence of psychiatric illness in the offspring. The proposed research will examine basic mechanisms underlying the contribution of prenatal stress to psychiatric disorders by investigating the function of placental microbes, and to determine how alterations in these microbes contributes to inflammation and regulation of growth factors in the intrauterine environment. Dr. Gur has established a mouse model of prenatal stress, which induces alterations in placental microbes and concomitant changes in inflammation and brain derived neurotrophic factor in utero, resulting in increased anxiety and cognitive changes in females, decreased social behavior in males, and longstanding changes in microbiome in both sexes. To our knowledge, this is the first evidence that prenatal stress alters microbes in utero. Our hypothesis is that dysbiosis in the placenta alters inflammation and BDNF, impacting the developing central nervous system, resulting in long-term microbiome and behavioral changes in the offspring. This hypothesis will be tested by pursuing these aims: 1) Determine whether placental microbes are viable, their origin, and, utilizing a germ-free mouse model, whether they are sufficient to induce behavioral changes; 2) Determine whether maternal stress is associated with immune dysregulation in the intrauterine environment; 3) Determine how stress-induced changes in microbiota alter BDNF in utero. Dr. Gur has assembled an outstanding team of mentors, including pioneers in stress and inflammation, and microbiome and health. The extensive resources of the Ohio State University and deep commitment and support of her Department and Institute, together with her formal plan for didactics in statistics, will further support Dr. Gur's goal of elucidating the mechanisms underlying the impact of prenatal stress on the developing offspring.